INTRODUCTION — Burkitt lymphoma (BL) is a highly aggressive B-cell neoplasm characterized by the translocation and deregulation of the c-myc gene on chromosome 8. Three distinct clinical forms of BL are recognized: endemic, sporadic, and immunodeficiency-associated. Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms as described below.

BL and Burkitt leukemia are classified as different manifestations of the same disease in the World Health Organization classification of hematologic malignancies; Burkitt-like lymphoma (BLL), is proposed as a morphologic variant of BL [1-5]. (See "Classification of the hematopoietic neoplasms".)

The epidemiology, clinical features, pathology, and diagnosis of BL will be reviewed here [6,7]. The pathobiology and treatment of BL are discussed separately (see "Pathobiology of the aggressive and highly aggressive non-Hodgkin lymphomas" and "Treatment of Burkitt leukemia/lymphoma".

EPIDEMIOLOGY — Burkitt lymphoma comprises 30 percent of non-endemic pediatric lymphomas, but less than 1 percent of adult non-Hodgkin lymphomas [8]. The incidence of BL in Africa is approximately 50-fold higher than that seen in the United States [9]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)

The endemic and sporadic clinical variants of BL differ geographically. The endemic (African) variant is found in equatorial Africa while the sporadic variant is seen in the United States and Western Europe. Endemic and sporadic BLs are both most common in children; the median age is younger in patients with the endemic form. BL is rare in adults, typically seen in patients less than 35 years of age, and is virtually always the non-endemic form [4]. In all groups, the majority of patients are male with a 3 or 4:1 male:female ratio [10].

In HIV positive patients, BL typically affects those with a relatively high CD4 count and no opportunistic infections. In comparison to the majority of other HIV-associated lymphomas, the rate of BL in the HIV-positive population has not decreased with the advent of highly active anti-viral therapy (HAART).

Cases classified as Burkitt-like lymphoma (BLL) are also rare. These patients have a median age of 55, also with a male predominance.

CLINICAL FEATURES — Patients with BL present with rapidly growing tumor masses and often have evidence of tumor lysis with a very high serum lactate dehydrogenase (LDH) concentration and elevated uric acid levels. Central nervous system (CNS) and bone marrow involvement is seen in approximately 15 and 30 to 40 percent, respectively. Three distinct clinical forms of BL are recognized: endemic, sporadic, and immunodeficiency-associated [6,11]. Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms:

• The endemic (African) form usually presents as a jaw or facial bone tumor (picture 1) that spreads to extranodal sites including the mesentery, ovary, testis, kidney, breast, and especially to the bone marrow and meninges.
• The nonendemic (sporadic) form usually has an abdominal presentation, most often with massive disease and ascites, involving the distal ileum, stomach (picture 2), cecum and/or mesentery, kidney, testis, ovary, breast, bone marrow, or central nervous system. Presenting symptoms can include those related to bowel obstruction or gastrointestinal bleeding, often mimicking acute appendicitis or intussusception.
• Immunodeficiency-related cases more often involve lymph nodes; both these and sporadic cases may present with blood involvement (see "AIDS-related lymphomas: Systemic lymphoma".

Burkitt-like tumors involve lymph nodes, the nasopharynx, and GI tract. Occasionally BLL presents as a solitary bone tumor. Like BL, these tumors have a high propensity to invade the bone marrow and central nervous system. Serum LDH concentrations are often elevated and B symptoms are present in about one-third of patients. (See "Pathophysiology and clinical features of leptomeningeal metastases (carcinomatous meningitis)".)

PATHOLOGY — BL cells are the neoplastic counterparts of a subset of normal activated germinal center B-cells [12]. This is supported by studies of normal lymphoid tissues, including the observation that CD10, BCL-6, several B-cell activation antigens, and the BL-associated glycolipid antigen CD77 are detected in the germinal centers of lymph nodes, and that BL have somatic mutations of their immunoglobulin genes like normal germinal center B-cells.

Histology — BL tumor cells are monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm (picture 3). Cytologically, Burkitt lymphoma (BL) cells resemble the small non-cleaved cells within normal germinal centers of the secondary lymphoid follicle. Prominent cytoplasmic lipid vacuoles are usually evident on imprints or smears. Although the Burkitt-like lymphoma (BLL) variant is similar to typical BL, the cells have greater pleomorphism [13].

There is an extremely high rate of proliferation as well as a high rate of apoptotic cell death. This results in two characteristic findings:

• The growth fraction of these lymphomas is very high, with frequent mitotic figures being seen and the fraction of Ki-67+ (MIB-1+) cells approaching 100 percent (see below).
• A "starry-sky" pattern is usually present, imparted by numerous benign macrophages that have ingested apoptotic tumor cells (ie, tingible body macrophages, (picture 3 and picture 4).

Immunophenotype — BL cells express surface IgM and B-cell-associated antigens (CD19, CD20, CD22, CD79a), as well as CD10, HLA-DR, and CD43 [14-19]. They lack CD5, bcl-2, and typically lack CD23 [20]. They show nuclear staining for BCL-6 protein, which is independent of bcl-6 gene rearrangement [21].

Expression of CD21, the Epstein-Barr virus (EBV)/C3d receptor is dependent upon EBV status of the tumors. The endemic BLs, which are EBV positive, express CD21, whereas the vast majority of non-endemic BL are EBV negative and lack CD21 expression. BL generally lack the adhesion molecules LFA-1 (CD11a/CD18), p150/95 (CD11c), and CD44 as reported in the literature. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)

The immunophenotype of the BLLs is very similar to BL, although expression of surface immunoglobulin (sIg), CD10 and CD21 is more variable. The immunophenotype of BLL as defined in the WHO classification has not been determined in prospective studies.

Genetic features

Translocations involving the c-MYC oncogene — In virtually all studies, BL is associated with a translocation between the long arm of chromosome 8, the site of the c-MYC oncogene (8q24), and one of three locations on Ig genes [22-29]:

• The Ig heavy chain gene on chromosome 14 : t(8;14)
• The kappa light chain gene on chromosome 2: t(2;8)
• The lambda light chain gene on chromosome 22: t(8;22).

In African (endemic) cases, the breakpoint on chromosome 14 involves the heavy chain joining region, while in non-endemic cases, the translocation involves the heavy chain switch region [23,30]. In endemic cases, the breakpoint in chromosome 8 usually lies adjacent to c-myc, while in sporadic cases it often lies in intron 1 within the gene. In one study, cases classified as Burkitt-like frequently had dual c-MYC and BCL-2 translocation (ie, "double hit" lymphomas); such cases had an extremely poor clinical outcome [31]. Cytogenetic and molecular genetic analyses of cases classified as BLL according to the WHO proposal are not available.

Other genetic abnormalities — Immunoglobulin heavy and light chain genes are rearranged. Studies of the immunoglobulin variable region genes show conflicting results: one study reported unmutated genes [32], while others report somatic mutations and intraclonal heterogeneity, consistent with ongoing mutations [33-35].

Mutations in the 5' noncoding region of the BCL-6 gene, similar to those seen in DLBCL, have been reported in 25 to 50 percent of the cases [36]. Most African cases contain clonal EBV genomes, as do 25 to 40 percent of the cases associated with acquired immune deficiency syndrome [37].

In a study involving 33 children and 37 adults with BL, in which all subjects had translocations involving chromosome 8, additional abnormalities were present in 81 and 73 percent of the children and adults, respectively [38]. The most commonly observed abnormalities involved chromosomes 1, 6, 13, 17, and 22. Of these, only abnormalities of chromosome 17 were poor prognostic features in adults.

DIAGNOSIS — The diagnosis of BL is based upon the pathologic evaluation of involved tissue, usually an abdominal mass. Histology reveals monomorphic, medium-sized cells with basophilic cytoplasm and a high proliferation fraction with the Ki-67 fraction approaching 100 percent. Cytogenetic analysis demonstrates a translocation involving the c-myc gene on chromosome 8. Rearrangements involving c-MYC can usually be detected by routine cytogenetics, but can also be demonstrated by FISH using fluorescent probes that are commercially available.

Whether c-MYC rearrangement is essential for the diagnosis has been thrown into question by studies showing that up to 5 percent of tumors with features that are otherwise typical of BL lack c-MYC rearrangements [39,40]. In the new WHO classification of lymphoid neoplasms, the diagnosis of BL is permitted in the absence of c-MYC rearrangement if all other morphologic, immunophenotypic, and genetic findings support the diagnosis [5].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for BL includes other tumors that can present as abdominal masses and other types of non-Hodgkin lymphoma. In children, the Wilms' tumor and neuroblastoma are the most common intraabdominal tumors; others include other forms of lymphoma, leukemias with extensive extramedullary involvement, hepatic tumors, ovarian tumors, and soft tissue sarcomas. Wilms' tumor and neuroblastoma occur more commonly in infants, whereas leukemic or lymphomatous involvement of the liver, spleen, or retroperitoneal lymph nodes occurs more commonly in older children.

Among the other types of non-Hodgkin lymphoma the most likely to be difficult to differentiate from Burkitt lymphoma are lymphoblastic lymphoma, blastic mantle cell lymphoma (which mimics the appearance of lymphoblastic lymphoma) and diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma — Although most cases present no problem in diagnosis, some BL cases may have larger cells or an admixture of centroblast- or immunoblast-like cells, resulting in morphologic overlap between BL and diffuse large B-cell lymphoma (DLBCL). These borderline cases have been referred to as "non-Burkitt" [41] or "Burkitt-like" and are associated with a high degree of inter- and intra-observer variation among hematopathologists (picture 5) [1,42]. In children and HIV+ patients, these tumors often have c-MYC translocations and behave similarly to typical BL, while in adults, cases classified as non-Burkitt lymphomas more often have BCL-2 gene rearrangements and are thought to represent an aggressive variant of DLBCL [13].

The 2008 version of the WHO classification system provides an overlap category termed "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" [5]. Some tumors in this group were previously classified as "Burkitt-like" lymphoma. The category is not homogeneous, but encompasses several types of aggressive B lymphoma that are difficult to place into the BL or DLBCL categories. These include lymphomas comprised of a mixture of large cells resembling DLBCL and smaller cells resembling BL, and tumors that more closely resemble BL morphologically but which have atypical immunophenotypic or genetic features. c-MYC rearrangements may be present, but these are often complex (instead of the simple translocations associated with BL) and sometimes associated with other genetic aberrations that are not seen in BL, such as the t(14;18) or rearrangements involving BCL6. This category does not include tumors that have typical DLBCL morphology but demonstrate the c-MYC rearrangement. Based on expression profiling data that suggest that up to five percent of otherwise typical BL lack c-MYC rearrangements, it is also acceptable to make a diagnosis of BL in tumors that lack a detectable c-MYC rearrangement, but are typical of BL in all other respects [39,43,44].

Features that exclude the diagnosis of BL include the presence of additional cytogenetic abnormalities, such as BCL-6 gene rearrangements or t(14;18); Ki-67 staining in less than 95 percent of the tumor cells, and positivity for BCL-2 (which is present in most DLBCLs and usually absent from Burkitt lymphoma). (See "Clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

Lymphoblastic lymphoma — Lymphoblastic lymphoma is another highly aggressive lymphoma that superficially resembles Burkitt lymphoma histologically. However, BL cells differ from lymphoblastic lymphoma cells in several respects; they have intermediate sized oval or round nuclei, more dispersed chromatin, several distinct nuclei, and more abundant cytoplasm. Also, lymphoblastic lymphomas express TdT, are often of T cell phenotype, and when of B cell origin fail to express surface immunoglobulin. Thus, flow cytometry or immunohistochemistry can distinguish BL from lymphoblastic lymphoma with a high degree of certainty.

Mantle cell lymphoma, blastic variant — Mantle cell lymphoma (MCL) is a lymphoma of adults, and does not enter into the differential in children. The morphology of the tumor cells usually resembles that of lymphoblastic lymphoma closely. It has the same immunophenotype as typical mantle cell lymphoma, being CD5 positive, cyclin D1 positive, CD10 negative, and BCL-6 negative, all of which distinguish this tumor from BL.

SUMMARY

• Burkitt lymphoma (BL) is a highly aggressive B-cell neoplasm that can present in one of three distinct clinical forms: endemic, sporadic, and immunodeficiency-associated. Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms. (See 'Introduction' above.)

• BL comprises 30 percent of non-endemic pediatric lymphomas, but less than 1 percent of adult non-Hodgkin lymphomas. The endemic variant is found in equatorial Africa while the sporadic variant is seen in the United States and Western Europe. Endemic and sporadic BLs are both most common in children and the majority of patients are male. (See 'Epidemiology' above.)

• Patients with BL present with rapidly growing tumor masses and often have evidence of tumor lysis. The endemic form presents as a jaw or facial bone tumor that spreads to extranodal sites while the nonendemic (sporadic) form has an abdominal presentation, most often with massive disease. Immunodeficiency-related cases more often involve lymph nodes. (See 'Clinical features' above.)

• BL tumor cells are monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm (picture 3). Prominent cytoplasmic lipid vacuoles are usually evident on imprints or smears. There is an extremely high rate of proliferation as well as a high rate of apoptotic cell death as evidenced by a Ki-67+ (MIB-1+) cells fraction approaching 100 percent and a "starry-sky" pattern. (See 'Histology' above.)

• BL cells express surface IgM and B-cell-associated antigens (CD19, CD20, CD22, CD79a), as well as CD10, HLA-DR, and CD43. They lack CD5, bcl-2, and typically lack CD23. (See 'Immunophenotype' above.)

• BL is strongly (but not uniformly) associated with a translocation between the long arm of chromosome 8, the site of the c-MYC oncogene (8q24), and one of three locations on Ig genes: t(8;14), t(2;8), or t(8;22). (See 'Genetic features' above.)

• The diagnosis of BL is based upon the pathologic evaluation of involved tissue, usually an abdominal mass. (See 'Diagnosis' above.)

• The differential diagnosis for BL includes other tumors that can present as abdominal masses and other types of non-Hodgkin lymphoma. Among the other types of non-Hodgkin lymphoma the most likely to be difficult to differentiate from Burkitt lymphoma are lymphoblastic lymphoma, the blastic variant of mantle cell lymphoma, and diffuse large B-cell lymphoma. (See 'Differential diagnosis' above.)